1. Field of the Invention
The invention relates to the treatment and prevention of cancer.
2. Summary of the Related Art
CDK8, along with its closely related isoform CDK19, is an oncogenic transcription-regulating kinase (1-3). In contrast to better-known members of the CDK family (such as CDK1, CDK2, and CDK4/6), CDK8 plays no role in cell cycle progression. CDK8 knockout in embryonic stem cells prevents embryonic development (5), due to its essential role in the pluripotent stem cell phenotype (6) but CDK8 depletion does not inhibit the growth of normal cells (5, 7). The role of CDK8 in cancer is due to its unique function as a regulator of several transcriptional programs involved in carcinogenesis (1). CDK8 has been identified as an oncogene in melanoma (8) and colon cancer (7), the CDK8 gene being amplified in ˜50% of the latter cancers. Higher expression of CDK8 has been associated with worse prognosis in colon cancer (9). The known cancer-relevant activities of CDK8 include positive regulation of Wnt/β-catenin pathway (7, 11), growth factor-induced transcription (12) and TGFβ signaling (13). CDK8 was also shown to maintain the pluripotent phenotype of embryonic stem cells and has been associated with the cancer stem cell phenotype (6). DNA-damaging chemotherapeutic drugs induce TNFα, an activator of the transcription factor NFκB (14), in endothelial cells and in other cancer-associated stromal elements. Stroma-derived TNFα acts on tumor cells, where it induces NFκB-mediated production of related tumor-promoting cytokines CXCL1 and CXCL2. CXCL1/2 attract myeloid cells to the tumor, by binding to CXCR2 receptor on the myeloid cell surface. Myeloid cells then secrete small calcium-binding proteins S100A8 and A9 that are associated with chronic inflammation and cancer. S100A8/9 act on tumor cells, promoting both their metastasis and survival of chemotherapy (15). PCT/US12/55064 teaches that CDK8/19 inhibitors inhibit induction of transcription factor NFκB, which mediates the production of multiple tumor-supporting proteins and inflammatory cytokines, and that CDK8/19 inhibitors in particular inhibit NFκB-mediated induction of CXCL1 and CXCL2. US Patent Publication 20120071477 teaches that CDK8/19 inhibitors also prevent the induction of paracrine tumor-promoting activities by DNA damage in normal fibroblasts, and inhibit HIV replication and β-catenin signaling.
US patent applications 20040180844 and 20040180848 claim “A method of killing a cancer cell, the method comprising contacting the cancer cell with an inhibitor of a gene selected from the group consisting of CDK8, STK33, PRKCM, PRKACA, ACVR1B, CDK5R1, CDC42BPB, MPP6, and CDC42BPA”, on the basis of a finding that transfection with siRNAs targeting CDK8 and certain other genes induces toxicity in a lung carcinoma cell line. However, this observation does not indicate that inhibition of the same genes would not be generally toxic to the organism and does not offer mechanistic rationale for inhibiting CDK8 in cancer treatment.
US Patent Publications 20120071477 discloses selective inhibitors of CDK8 and its isoform, CDK19. There is a need for more soluble and more potent compounds and methods for selectively inhibiting CDK8. There is also a need to better understand the role of CDK8 in cancer to provide additional uses of CDK8 inhibitors.